Fluoroquinolone Resistance in E. coli
Fluoroquinolones are among the most potent, widely prescribed, broad-spectrum oral antibiotics. Quinolones kill bacteria by targeting the two type-2 topoisomerases, gyrase and topoisomerase IV. These essential enzymes pass DNA strands through each other and are required for DNA replication, recombination, transcription, chromosome segregation, and maintenance of DNA supercoiling levels (more). Quinolones stabilize the normal, transient topoisomerase-DNA cleavage intermediate. With a mechanism that is not well understood, DNA tracking by processes such as replication or transcription collide with the drug-stabilized topoisomerase-DNA adducts to cause cell death.
To reach their cellular targets, drugs must first penetrate the defense system of the bacterial cell. Not only are cells well-equipped to withstand treatment with drugs, but it has become increasingly clear that bacteria undergo genetic alteration to become resistant to drugs. Although drug resistant bacteria are one of the most critical problems facing the medical community today, surprisingly little is known about how cells resist drugs. Therefore, the goal of our research is to determine how the model system Escherichia coli respond to and resist treatment with the quinolone antibiotics. Ultimately, our results may be used to design better chemotherapeutics to help prevent the worldwide problem of drug resistance.
Current Lab Members Working on This Project:
Michelle C. Swick
Collaborators:
Robert Atmar, M.D.
Richard J. Hamill, M.D.
Javier Rojo, Ph.D.
David Steffen, Ph.D.
Richard Sucgang, Ph.D.
James Versalovic, M.D.,Ph.D.
Funding:
1998-2002 Burroughs Wellcome Fund New Investigator Award (www.bwfund.org)
1998-1999 Curtis Hankamer Research Award
2001-2005 National Science Foundation (MCB 0090880)
2003-2006 Houston Area Molecular Biophysics Program (T32 GM08280)
2004-2006 Burroughs Wellcome Fund Research Grant (1005267) (www.bwfund.org)
2004-present Pharmacoinformatics Training Program (NIH T90 DK070109)
2004-2010 National Institutes of Health (RO1 AI054830)